Numerous studies have demonstrated that both the risk of coronary heart disease (CHD) in humans and the severity of experimental atherosclerosis in animals are inversely correlated with serum HDL cholesterol (HDL-C) concentrations (Russ et al., Am. J. Med., 11 (1951) 480-483; Gofman et al. Circulation. 34 (1966), 679-697; Miller and Miller, Lancet, 1 (1975), 16-19; Gordon et al., Circulation, 79 (1989), 8-15; Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381; Badimon et al., Lab. Invest., 60 (1989), 455-461). Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke. Angiographic studies have shown that elevated levels of some HDL particles in humans appear to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (Miller et al., Br. Med. J., 282 (1981), 1741-1744).
There are several mechanisms by which elevated HDL levels may protect against the progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al., Arteriosclerosis, 6 (1986), 434-441). Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissue of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res., 9 (1968), 155-167). This has been supported by experiments showing the efficient transfer of cholesterol from HDL to the liver (Glass et al., J. Biol. Chem., 258 (1983), 7161-7167; McKinnon et al., J. Biol. Chem., 261 (1986), 2548-2552). In addition, HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem., 253, (1978), 1834-1841; Lagocki and Scanu, J. Biol. Chem., 255 (1980), 3701-3706; and Schaefer et al., J. Lipid Res., 23 (1982), 1259-1273). More recently, as a possible mechanism for protection against the development of atherosclerosis, Cockerill et. al. Arterioscler., Thromb., Vasc. Biol, 15, (1995), 1987-1994 have demonstrated that plasma HDL's inhibit cytokine-induced expression of endothelial cell adhesion molecules (VCAM-1 and ICAM-1) in a concentration dependent and cell specific manner. Accordingly, it follows that compounds which increase HDL cholesterol concentrations would be useful as anti-atherosclerotic agents, useful particularly in the treatment of dyslipoproteinimias and coronary heart disease.
Certain indole-1-carbothioic acid amides and their derivatives have been disclosed in the prior art. For example, the use of indole-1-carbothioic acid amides as intermediates in the synthesis of benzothiazoles has been discussed in J. Het. Chem., 28 (1991) 759-763. J. Org. Chem., 33 (1968), 4551-4554, describes the synthesis of indole-1-carbothioic acid amides. However, no utility for the compound is stated. Lastly, the use of a series of indole-1-carbothioic acid amides as inhibitors of platelet aggregation is disclosed in Chem. Pharm. Bull., 21 (1973), 1151-1155. However, the prior art contains no disclosure or suggestion of the use of the present substituted indole-1-carbothioic acid amides, nor their use as antiatherosclerotic agents.